Author ORCID Identifier

https://orcid.org/0000-0002-5241-223X

Semester

Fall

Date of Graduation

2025

Document Type

Dissertation

Degree Type

PhD

College

School of Pharmacy

Department

Pharmaceutical Sciences

Committee Chair

Sharan Bobbala

Committee Member

William Petros

Committee Member

Ahmad Hanif

Committee Member

Salik Hussain

Committee Member

Nicholas Karabin

Abstract

Nanoparticle-based drug delivery has made tremendous advancements in the last decade. However, several critical factors, including precision drug delivery at the site of interest, long-term storage stability, and controlling release profiles of drugs in the systemic circulation, need to be addressed for successful clinical translation of nanomedicine. This dissertation presents novel carbohydrate-based nanoparticles that achieve precise intracellular delivery and therapeutic release at the disease site. We present the formulation and optimization of polymeric and polymer-lipid hybrid nanoparticles that enable precision intracellular delivery and passive accumulation of therapeutics in the bone marrow. Intracellular delivery is highly impactful and sought after. One way this can be addressed is by using stimuli-responsive materials, which often feature organic backbones, such as lipids and polymers. Here, acetalated dextran (Ac-Dex) and acetalated inulin (Ac-Inulin) are utilized as pH-responsive carriers. Ac-Dex and Ac-Inulin are naturally occurring carbohydrates that have been chemically modified with an acid-labile acetal group. The nanoparticles retain their integrity and encapsulated payloads under non-targeted physiological conditions; however, once exposed to the desired acidic environment, such as the endolysosome or tumor microenvironment, they rapidly dissociate to release the therapeutic payload. To demonstrate clinical translatability, we use B-cell acute lymphoblastic leukemia as a disease model. However, the kinetics of nanoparticle retention inside the bone marrow and the delivery efficiency of therapeutics in the bone marrow microenvironment are often understudied. We achieve selective bone marrow delivery through the integration of oleic acid, a fatty acid found naturally in the bone marrow, onto Ac-Dex nanoparticles. Ultimately, our work establishes novel carbohydrate-based nanoparticles as a platform that can achieve intracellular release with precise degradation, while also serving as a modular platform that can integrate oleic acid to guide bone marrow accumulation for therapeutic delivery to treat hematological malignancies.

Download

Share

COinS